Autoimmune diseases associated with type 1 diabetes

Type 1 diabetes is itself an autoimmune disease: your immune system mistakenly attacks the beta cells in the pancreas, the ones that produce insulin. The same inherited genetic predisposition (especially the genes in the HLA, human leukocyte antigen region) can affect other organs too [1]. The same is true of the loss of immune tolerance, the mechanism by which the body learns not to attack itself. In practice, type 1 diabetes signals a tendency of the immune system to attack the body's own tissues. That tendency does not always stay limited to the pancreas [2].

The most commonly targeted are the thyroid, the gut and the stomach. For this reason, the autoimmune diseases associated with type 1 diabetes are looked for periodically, even in the absence of symptoms. Early detection allows more effective treatment and prevents complications from developing [2].

Autoimmune polyendocrine syndrome (abbreviated APS) brings together several diseases in which the immune system attacks multiple glands and organs in the same person. The most commonly affected are the glands that produce hormones, such as the thyroid, the adrenal glands and the pancreas. Hence the name: "poly" means several, and "endocrine" refers to the hormonal glands [3].

An important practical aspect is that these conditions do not all appear at the same time. Years or even decades can pass between one disease and the next. APS is therefore a diagnosis that evolves over a lifetime and requires continuous monitoring. There are several subtypes of APS (1, 2 and 3), which differ in the age of onset, the genetic cause and the combination of diseases [3].

APS-1 is the rarest form and usually appears in childhood. It is caused by a single defective gene (called AIRE) and is recognized by three typical signs:

• repeated fungal infections of the skin and mucous membranes;
• poorly functioning parathyroid glands (with a fall in calcium);
• Addison's disease (adrenal insufficiency).

Type 1 diabetes can also appear in some of these patients [4].

APS-2 is the most common form and appears in adults, especially in women. It involves several genes and, in the classic definition, includes Addison's disease, to which autoimmune thyroid disease and/or type 1 diabetes are added. APS-3 always includes thyroid involvement plus another autoimmune disease (such as type 1 diabetes) but without Addison's disease. The criteria for these subtypes differ from one author to another, however, so classifying a person is not always clear-cut. Most people who have type 1 diabetes and a thyroid disease at the same time fall into APS-3 [3].

Hashimoto's thyroiditis is the most common autoimmune disease associated with type 1 diabetes. The immune system attacks the thyroid, which sometimes leads to a smaller thyroid that produces too few thyroid hormones (hypothyroidism). The specific antibodies (anti-TPO, anti-TG) appear in the blood many years before thyroid function begins to decline [5]. Such thyroid autoantibodies are found in about one in four patients with type 1 diabetes [6].

The signs of hypothyroidism include fatigue, feeling cold and, in children, slowed growth. They do not appear, however, as long as thyroid function is normal, and the mere presence of antibodies causes no symptoms. For you, an important aspect is that an underactive thyroid slows the clearance of insulin and reduces the release of glucose from the liver. It can therefore increase the risk of hypoglycemia. If hypoglycemia becomes more frequent, talk to your doctor about adjusting your insulin doses. Treatment consists of replacing the missing hormone with levothyroxine, at the dose set and adjusted by your doctor based on your test results. The thyroid is checked shortly after the diagnosis of type 1 diabetes and then annually, as the figure below shows [5].

Yes, but much more rarely than Hashimoto's thyroiditis. Graves' disease is, in a way, the opposite of Hashimoto's thyroiditis: the thyroid becomes overactive (hyperthyroidism) because certain antibodies stimulate it to produce thyroid hormones in excess [5].

The signs of hyperthyroidism include weight loss despite a good appetite, palpitations, feeling hot, tremor, restlessness and, sometimes, bulging eyes. An overactive thyroid makes blood glucose harder to control, with a tendency to hyperglycemia. Both Graves' disease and Hashimoto's thyroiditis are forms of autoimmune thyroid disease and can, occasionally, affect the same person at different times in life [7].

Celiac disease is considerably more common in people with type 1 diabetes than in the general population. It is a reaction of the immune system to gluten — a protein in wheat, barley and rye — that damages the lining of the small intestine [8].

An important feature in people with type 1 diabetes is that celiac disease is often silent: many people have no digestive symptoms at all. That is why a blood test (anti-transglutaminase antibodies of the IgA type, together with total IgA) is recommended instead of waiting for symptoms to appear. Untreated, the disease can cause fatigue, anemia, reduced bone strength, poor growth in children and unexplained hypoglycemia, and the treatment is a gluten-free diet maintained for life [9].

Addison's disease (adrenal insufficiency) is, fortunately, very rare, but at the same time very dangerous. The immune system attacks the adrenal glands, which can no longer produce enough cortisol, a hormone essential for survival [3]. The signs of cortisol deficiency include persistent fatigue, weight loss, low blood pressure, dizziness on standing up and a craving for salt.

The skin darkens, especially in skin folds and on scars. A special warning sign for you, if you have type 1 diabetes, is repeated and unexplained hypoglycemia, accompanied by a decrease in insulin requirements. The explanation is that cortisol normally opposes insulin and raises blood glucose. Any of these signs requires prompt medical assessment, and the treatment consists of replacing the missing hormones [6]. Untreated, the lack of cortisol can lead to an adrenal crisis, a medical emergency. If vomiting, severe abdominal pain, extreme weakness or drowsiness appear, go to the emergency department without delay.

Yes. Vitiligo means well-defined white patches on the skin, which appear because the immune system destroys the cells that give the skin its color (melanocytes). This condition is more common in people with type 1 diabetes than in the general population [6].

Vitiligo often appears together with autoimmune conditions of the thyroid, the stomach or the adrenal glands. In itself, vitiligo does not affect the functioning of the internal organs. The unpigmented patches, however, burn easily in the sun and need protection, and the condition can affect self-image and emotional state. In addition, its presence signals a broader autoimmune tendency, which is useful to recognize and follow [10].

Pernicious anemia is a type of anemia caused by a lack of vitamin B12, which arises because of an autoimmune attack on the stomach. The immune system attacks the cells of the stomach, which can then no longer help absorb vitamin B12 from food [11].

The signs include fatigue, pallor, a burning tongue and neurological symptoms such as numbness or tingling (which can appear even before the anemia). It is one of the relatively common autoimmune associations in type 1 diabetes. It is not part of periodic screening, but signs like these prompt doctors to look for it early. Treatment consists of giving vitamin B12, at the dose set by your doctor [12].

Besides the common conditions, the immune system can occasionally attack other organs too. The liver (autoimmune hepatitis), the joints (rheumatoid arthritis or juvenile arthritis), the skin (psoriasis) or the hair (alopecia areata — patchy hair loss) can be affected [10].

Even rarer are the conditions involving the nerves and muscles (myasthenia gravis, multiple sclerosis) or the lack of an entire class of antibodies (IgA deficiency). The latter matters because it influences the way celiac disease is tested for. These associations are unusual, and testing for them is done according to symptoms, not routinely [13].

For the thyroid, testing is done shortly after the diagnosis of type 1 diabetes, then usually annually — or more often if symptoms appear or if antibodies are already present. In children and adolescents, celiac disease is looked for at diagnosis, again within the first two years and then after five years [14]. In adults, the test is done if symptoms, signs or laboratory results suggest it [15].

For the rarer conditions, such as Addison's disease, no routine screening is done, only when symptoms raise a suspicion. The general rule is continuous surveillance, throughout life, because a new autoimmune disease can appear at any time [2].

These associations can appear at any time in life, without there being an age after which the risk disappears. Some autoimmune diseases may already be present at the time of the type 1 diabetes diagnosis, but as a rule they appear years or decades later. That is precisely why continuous surveillance is so important [16].

There are, however, a few patterns: celiac disease tends to appear earlier, in the first years after diagnosis. Thyroid diseases, pernicious anemia and joint conditions become relatively more common with advancing age and with a longer duration of diabetes. Women are somewhat more likely to develop an additional autoimmune disease. Onset in early childhood is linked mainly with celiac disease, and later onset with thyroid disease [17].